Burden of axillary hyperhidrosis using a patient-reported outcome measure to assess impact on activities and bothersomeness

Burden of axillary hyperhidrosis using a patient-reported outcome measure to assess impact on activities and bothersomeness

Presenters: Pariser DM1, Hebert AA2, Drew J3, Quiring J4, Glaser DA5

Affiliations: 1Eastern Virginia Medical School and Virginial Clinical Research, Inc., Norfolk, VA; 2UTHealth McGovern Medical School, Houston, TX; 3Dermira, Inc., Menlo Park, CA; 4QST Consultations, Allendale, MI; 5Saint Louis University, St. Louis, MO

Introduction: Hyperhidrosis affects approximately 4.8 percent of the United States population, and approximately three-quarters of patients experience a negative psychological impact. Anxiety and depression are over 3.5 times more common among hyperhidrosis sufferers. The Axillary Hyperhidrosis Patient Measures (AHPM)­—the four-item Axillary Sweating Daily Diary (ASDD), two-item, child-specific version of ASDD [ASDD-C] for patients at least nine years old but less than 16 years old, six Weekly Impact (WI) items, and single-item Patient Global Impression of Change (PGIC)—were developed in consultation with the United States Food and Drug Administration (FDA) and in consideration of FDA patient-reported outcomes (PRO) guidance. Baseline values from two Phase III trials of an investigational axillary hyperhidrosis treatment, topical glycopyrronium tosylate (GT; formerly DRM04), were evaluated to characterize the burden of disease.

Methods: ATMOS 1 (DRM04-HH04, NCT02530281) and ATMOS 2 (DRM04 HH05, NCT02530294) were randomized, double-blind Phase III trials. Patients at least nine years of age with primary axillary hyperhidrosis for at least six months, gravimetrically measured sweat production of at least 50mg per five minutes in each axilla, ASDD axillary sweating severity item (Item 2) 4 or above (numeric rating scale 0 to 10), and Hyperhidrosis Disease Severity Scale (HDSS) Grade 3 or above were randomized 2:1 to GT or vehicle applied once-daily to each axilla for 28 days. Item 1 assessed the presence of underarm sweating and acted as a gatekeeper question for Item 2. ASDD Items 3 and 4 assessed impact and bother of axillary sweating (numeric rating scale 0–4). WI Items assessed the impact of axillary sweating (needing to change shirt during the day, needing to bathe at least once a day, feeling less confident, feeling embarrassed, avoiding interactions, kept from doing an activity on a weekly basis). ASDD items were scored as a weekly average of daily responses. Baseline ASDD item scores and proportion of patients with positive responses to WI items are reported.

Results: Among 697 randomized patients, 665 were at least 16 years of age and were asked Items 3 and 4 and WI items. For ASDD Item 2, 59.3 percent and 59.8 percent of patients had a score of 7 or above (moderately severe sweating) at baseline in ATMOS-1 and ATMOS-2, respectively. For Item 3, 69.4 percent and 71.7 percent had a score of 2 (moderate impact) or above. For Item 4, 77.8 percent and 77.4 percent had a score of 2 (moderate bother) or above. In both studies, a majority of patients reported being impacted by their excess sweating, with most having to avoid interactions or take additional measures (e.g., bathing more than once a day, changing shirts during the day) due to excessive sweating. Over 96 percent of patients experienced embarrassment due to underarm sweating.

Conclusion: In this analysis, over 69 percent and 77 percent of patients reported feeling moderately impacted and bothered by their axillary hyperhidrosis during daily activities at baseline. Nearly all patients (>96%) reported embarrassment, underscoring previously reported negative psychological impact of this underreported and underdiagnosed condition.

Perceptions regarding use of anti-tumor necrosis factor treatments for women of childbearing age among healthcare professionals

Perceptions regarding use of anti-tumor necrosis factor treatments for women of childbearing age among healthcare professionals

Presenters: Voorhees AV1, Afzali A2, Schwartzman S3, Ecoffet C4, Pisenti L5, Stark J5, Yassine M5, Abraham B6

Affiliations: 1Eastern Virginia Medical School, Norfolk, VA; 2The Ohio State University Wexner Medical Center, Columbus, OH; 3Hospital for Special Surgery, New York, NY; 4UCB Pharma, Brussels, Belgium; 5UCB Pharma, Smyrna, GA; 6Houston Methodist Hospital, Houston, TX

Background/Objective: For women with chronic inflammatory diseases (e.g., psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, inflammatory bowel disease), disease onset, diagnosis, and treatment initiation often overlap with peak reproductive years. High disease activity is associated with increased risk of pregnancy complications and adverse outcomes, and achieving disease control is therefore an important goal for the success of these pregnancies. Tumor necrosis factor antagonists (anti-TNFs) are effective treatments, but use among women of childbearing age (WoCBA) varies due to differing attitudes regarding their safety profiles versus benefits. This survey aimed to better understand perceptions and attitudes of healthcare professionals (HCPs) across different specialties regarding treatment of WoCBA patients with anti-TNFs during pregnancy and lactation.

Methods: An online survey was conducted in the United States on July 6, 2017, by SERMO RealTime. WoCBA was defined as women between the ages of 18 and 45 years. Survey participants included dermatologists (DM), gastroenterologists (GI), rheumatologists (RA) and obstetricians/gynecologists (OB).

Results: Two-hundred and fifty-six HCPs participated in the survey, including 53 DMs, 50 GIs, 50 RAs, 50 OBs. Half of the female patient population across specialties were WoCBA. DMs had the lowest proportion (27%) of female patients prescribed anti-TNFs (GI: 31%; RA: 43%). While physicians indicated being comfortable prescribing anti-TNFs for WoCBA patients, concerns were more prevalent once patients actively started family planning. DMs (57%) and OBs (62%) were more likely to recommend discontinuation of anti-TNFs before conception than GIs (36%) and RAs (46%); 45 percent of DMs and 54 percent of OBs agreed that WoCBA patients should stop anti-TNFs once they are pregnant (compared to <35% GIs and RAs). GIs (46%) and RAs (42%) agreed more strongly than DMs (15%) and OB (20%)on making disease control during pregnancy their priority . Only 17 percent of DMs felt that disease control reduces the risk of pregnancy complications and adverse outcomes, compared to GIs (52%), RAs (42%) and OBs (28%). More DMs and OBs than GIs and RAs believed patients who are breastfeeding should not take anti-TNFs, although a high degree of uncertainty was indicated. Overall, HCPs believed that more safety data during and after pregnancy are needed to feel more comfortable with prescribing anti-TNFs to WoCBA patients who are or might become pregnant in the future.

Conclusion: Our survey demonstrates the variability in clinical management of women with inflammatory or autoimmune diseases. Uncertainty about risks of anti-TNF use during pregnancy and lactation is common. Further research and multidisciplinary engagement among HCPs are needed to discuss and safely treat WoCBA.

Fundings/Disclosures: AVV: Consultant for: Dermira, Novartis, Celgene, AbbVie; board member: Dermira, Novartis, Celgene, AbbVie, Allergan, Derm Tech, Valeant, WebMD; ex-spouse pension: Merck; AA: Consultant for AbbVie, Takeda, UCB Pharma, research grant support from AbbVie, non-profit consultant and board member for IBD Horizons; SS: Consultant for Abbvie, Antares, Genentech, Janssen, Lilly, Novartis, Pfizer, Regeneron, Sanofi, UCB Pharma; speaker fees: Abbvie, Janssen, Genentech, Pfizer, UCB Pharma, Crescendo, Novartis; board member: Crescendo Biosciences, Discus Analytics, National Psoriasis Foundation; CE, LP, JS, MY: Employee of UCB Pharma; MC: Employee of Dermira Inc; BA: Grant/research support: Janssen, UCB Pharma; speaker’s fees: AbbVie, American Reagent, Janssen, UCB Pharma

Long-term results of investigator-assessed efficacy and safety of 200mg dose of sonidegib for locally advanced basal cell carcinoma: 30-month BOLT analysis

Long-term results of investigator-assessed efficacy and safety of 200mg dose of sonidegib for locally advanced basal cell carcinoma: 30-month BOLT analysis

Presenters: Migden M1, Lewis KD2

Affiliations: 1University of Texas MD Anderson Cancer Center, Departments of Dermatology, Division of Internal Medicine, and Head and Neck Surgery, Division of Surgery, Houston, TX; 2University of Colorado Denver, School of Medicine, Division of Medical Oncology, Denver, CO

Background/Objective: The 200mg dose of sonidegib was approved in 2015 in the European Union, Switzerland, Australia, and the United States for the treatment of patients with locally advanced basal cell carcinoma (laBCC) who are not amenable to curative surgery or radiation therapy. In both Switzerland and Australia, sonidegib is also approved for the treatment of metastatic BCC (mBCC). Sonidegib is a selective smoothened (SMO) inhibitor that blocks hedgehog pathway signaling. Approvals were based on results from the pivotal BOLT Phase II clinical trial (NCT01327053). Efficacy and safety data from BOLT were assessed by both investigator and central review. Here, we report the investigator-assessed efficacy and safety data of sonidegib 200mg QD from the 30-month analysis.

Methods: BOLT is a randomized, double-blind clinical trial that was conducted in 58 centers across 12 countries. Patients received either 200mg or 800mg of sonidegib once daily. Only the 200mg dose data will be presented here, as this dose was found in earlier studies to be more tolerable and equally as effective as the higher dose. As a primary endpoint, investigators evaluated objective response rate (ORR), which is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor evaluations were done using BCC-modified Response Evaluation Criteria In Solid Tumors (mRECIST) for laBCC. Sonidegib safety was monitored, including the monitoring of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

Results: In patients with laBCC who received sonidegib 200mg (n=66), the investigator-assessed ORR was 71 percent. Median overall survival was not reached at this time point, but the two-year overall survival rate was 93 percent. Tumor responses were durable with a median duration of response of 15.7 months. At the 30-month data cutoff, the median duration of PFS was 19.4 months. One death was reported in the 200mg dose arm of patients with laBCC, but it was not considered to be related to study treatment. The safety profile of sonidegib 200mg was manageable, and no new safety concerns were found compared to the earlier BOLT data analyses. In summary, 43 percent of patients experienced grade 3/4 adverse events and AEs requiring dose interruptions/reductions. AEs that led to discontinuation occurred in 30 percent of patients, and the most commonly reported AEs included muscle spasms (56%), alopecia (52%), and dysgeusia (47%).

Conclusion: In the BOLT 30-month analysis, sonidegib 200mg QD provided sustained efficacy and a continued long-term acceptable safety profile in patients with laBCC. Interestingly, both the median DOR and median PFS data were higher when assessed by central review compared to investigator review. Given the stringent criteria used to assess tumor responses in the BOLT trial, these data support the use of sonidegib 200mg QD in patients with laBCC when used according to local treatment guidelines.

Safety and efficacy of A-101 hydrogen peroxide topical solution 40% in adults with seborrheic keratosis: results from the Phase III, randomized, double-blind, vehicle-controlled, parallel-group study

Safety and efficacy of A-101 hydrogen peroxide topical solution 40% in adults with seborrheic keratosis: results from the Phase III, randomized, double-blind, vehicle-controlled, parallel-group study

Presenters: Draelos ZD1, Kempers SE2, Smith SR3, Wilson DC4; Powala C5, Bradshaw M6; Estes E5; Shanler S5

Affiliations: 1Dermatology Consulting Services, High Point, NC; 2Minnesota Clinical Study Center, Fridley, MN; 3California Dermatology & Clinical Research Institute, Encinitas, CA; 4The Education and Research Foundation, Inc., Lynchburg, VA; 5Aclaris Therapeutics, Malvern, PA

Objective: Seborrheic keratosis (SK) is one of the most common benign skin lesions, affecting over 80 million Americans, yet there is no United States Food and Drug Administration (FDA)-approved treatment available. The purpose of this study was to evaluate the safety and efficacy of a proprietary 40% hydrogen peroxide topical solution (A-101) versus its matching vehicle for the treatment of seborrheic keratosis.

Design: Adults with four eligible SK lesions identified by the study investigator were randomized 1:1 to A-101 or a matching A-101 vehicle. Eligible lesions were stable, typical SKs, measuring 5 to 15mm in both width and length and less than 2mm in thickness. Subjects were required to present with at least one lesion on the trunk or extremities and at least one lesion on the face. All treatments were performed by a non- physician sub-investigator to maintain blinding. All lesions were treated on Day 1. Previously treated SK lesions with a Physician’s Lesion Assessment score over 0 were re-treated on Day 22 (PLA scale: 0=clear, 1=near clear, 2=thickness ?1mm, and 3=thickness>1mm). At Day 106, the investigator assessed the lesions using the validated PLA scale.

Results: Total of 450 subjects were enrolled. At Day 106, significantly more subjects receiving A-101 (intent-to-treat ITT population) completely cleared (PLA=0) all four lesions (4% vs. 0%, P<0 .002) and 3 of 4 lesions (13.5% vs. 0%, P<0.0001) versus vehicle in the primary and secondary endpoints, respectively. In the a priori exploratory analyses (per protocol population [PPP], n=439), significantly higher mean per-subject percentage of lesions achieving clear or near clear (PLA?1) was observed in the A-101 arm (47.5% vs. 10.2%; P<0.0001). Significantly higher mean per-subject percentage of facial lesions achieving clear or near clear (PLA?1) was also observed (64.4% vs.15.0% at Day 106; P<.0001). Adverse events were comparable between groups.

Local skin reactions were predominantly mild and generally resolved by Day 106. At all visits, atrophy, erosion, hypopigmentation, scarring, or ulceration were reported for at least four percent of lesions.

Conclusion: A-101, a 40% hydrogen peroxide topical solution, is a safe, effective, and well-tolerated treatment for SK. If approved, it would offer the first FDA-approved topical treatment for SK.

Cemiplimab (REGN2810), a fully human anti-PD-1 monoclonal antibody, for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Initial safety and efficacy from expansion cohorts of Phase I study

Cemiplimab (REGN2810), a fully human anti-PD-1 monoclonal antibody, for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Initial safety and efficacy from expansion cohorts of Phase I study

Presenters: Papadopoulos KP1,Owonikoko TK2, Johnson ML3, Bra?a I4, Gil-Martin M5, Perez RP6, Moreno V7, Salama AK8, Calvo E9,Yee NS10, Safran H11, González-Martín A12, Aljumaily R13, Mahadevan D14, Mohan KK15, Li J16, Stankevich E15, Israel Lowy I15, Fury MG15, Homsi J17

Affiliations: 1South Texas Accelerated Research Therapeutics, San Antonio, TX; 2Emory Winship Cancer Institute, Atlanta, GA; 3Sarah Cannon Research Institute, Nashville, TN; 4Vall D’HebronInstitute of Oncology, Barcelona, Spain; 5InstitutCatalàd’Oncologia, Barcelona, Spain; 6Unversity of Kansas, Fairway, KS; 7START Madrid Fundacion Jimenez Diaz, Madrid, Spain; 8Duke University Medical Center, Durham, NC; 9START Madrid, Hospital Madrid Norte Sanchinarro, Madrid, Spain; 10Penn State Cancer Institute, Hershey, PA; 11Miriam Hospital, Providence, RI; 12Formerly of MD Anderson International España, Madrid, Spain; 13University of Oklahoma Health Sciences Center, Oklahoma City, OK; 14Formerly of University of Arizona Cancer Center, Tucson, AZ; 15Regeneron Pharmaceuticals Inc., Tarrytown, NY; 16Regeneron Pharmaceuticals Inc., Basking Ridge, NJ; 17Formerly of Banner MD Anderson Cancer, Gilbert, AZ.

Background/Objective: Cemiplimab (REGN2810) is a human immunoglobulin G4 monoclonal antibody directed against PD-1.1. Phase I results from the first 60 patients with advanced solid tumors showed no dose-limiting toxicities. The most common treatment-related adverse events (AEs) in these patients were fatigue (28%), arthralgia (12%), and nausea(12%); the overall response rate was 18 percent. Cemiplimab 3mg/kg every two weeks (Q2W) was selected for further study in Expansion Cohorts. As of April 27, 2017, 392 patients have been enrolled in the Phase I study. The coprimary objectives of the CSCC Expansion Cohorts of this Phase I open-label study were to characterize the safety and tolerability of intravenous cemiplimab 3mg/kg and to evaluate the efficacy of cemiplimab by measuring overall response rate (ORR).

Methods: CSCC Expansion Cohorts (NCT02383212): Cohort 7 enrolled 10 patients with mCSCC, and Cohort 8 enrolled 16 patients with unresectable locally and/or regionally advanced CSCC. All patients received cemiplimab 3mg/kg Q2W for up to 48 weeks (if no progression or intolerance), followed by post-treatment follow-up. There was an option for re-treatment for patients who experienced disease progression during post-treatment follow-up, but no CSCC patients required this re-treatment option at the time of this study. All patients underwent tumor imaging every eight weeks, and response assessments were per RECIST 1.1. Research biopsies were performed at baseline and at Day 29. Subjects included scored a 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status, had a measurable disease by RECIST 1.1, had adequate organ function (bone marrow, kidney, liver), were in the mCSCC(M1): Expansion Cohort 7 and/or the unresectablelocally and/or regionally advanced CSCC (M0): Expansion Cohort 8. Exclusion criteria included presence of an autoimmune disease within five years, active brain metastases, or other invasive malignancy within five years (no exclusion for tumors considered cured by localized treatment), immunosuppressive doses of steroids (>10mg prednisone daily or equivalent), systemic antitumor treatment within four weeks of initial dose of cemiplimab, history of solid organ transplant, and tumors of lip or eyelid not eligible for CSCC cohorts.

Results: Investigator-assessed preliminary ORR (complete response [CR] + partial response [PR] + one unconfirmed PR) by RECIST 1.1 was 46.2 percent (12/26 patients; 95% confidence interval [CI]: 26.6–66.6; intent-to-treat [ITT] population). Disease control rate (DCR = ORR + stable disease [SD]) was 69.2 percent (18/26 patients; 95% CI: 48.2–85.7). Cemiplimab also produced rapid, deep, and durable tumor reductions in target lesions in both cohorts. As of April 27, 2017 (data cut-off date), 26 patients (median age, 73 years) from the CSCC expansions cohorts have been treated with cemiplimab. A total of 17 of 21 evaluated tumors (81%) were positive (?1%) for tumor expression of PD-L1 by immunohistochemistry. There was no apparent association between PD-L1 immunohistochemistry results and objective responses. The most common treatment-emergent adverse event (AEs) were fatigue, occurring among six patients. Two patients discontinued study treatment after treatment-related AEs: an 86-year-old woman developed a Grade 3 rash after three doses (she continued post-treatment follow-up) and an 88-year old male withdrew consent following Grade 3 transaminase elevation and Grade 2 fatigue after six doses. There were two deaths within 30 days of last dose of study drug, both considered unrelated to study drug.

Conclusion: This is the first prospective study of a PD-1 inhibitor in patients with advanced CSCC. Cemiplimab was generally well tolerated in CSCC in this predominantly older population. Both locally advanced and mCSCC are highly responsive to cemiplimab (combined ORR 46.2%), and durability is emerging. Eighty-one percent of pre-treatment tumor samples were PD-L1 positive. A unifying characteristic of cutaneous malignancies appears to be responsiveness to immune checkpoint inhibition. A Phase II study is ongoing in patients with unresectablelocally advanced and mCSCC(NCT02760498).

Funding/Disclosures: This study was funded by Regeneron Pharmaceuticals Inc, and Sanofi. Dr. Papadopoulos has received institutional research funding from Regeneron and Sanofi. Taofeek Owonikoko holds a consulting/advisory role for Regeneron. Melissa Johnson receives research funding from Regeneron. Raymond Perez receives institutional research funding from Regeneron. Emiliano Calvo receives institutional research funding from Sanofi. Nelson Yee receives institutional research funding from Regeneron. Kosalai Mohan, Jingjin Li, Elizabeth Stankevich, Israel Lowy, Matthew Fury, are stockholders and employees of Regeneron Pharmaceuticals, Inc. Matthew Fury also receives research funding, institutional patents, royalties, and other intellectual property from Regeneron. Jade Homsi receives research funding from Regeneron.

Lasers: Red vs Blue in PDT

Its Blue

A study reported late last year was carried out to determine whether prior microneedling would enhance the penetration of topical aminolevulinic acid HCl (Levulan) and thus enhance photodynamic therapy (PDT) and possibly also result in a better cosmetic outcome vs PDT alone in patients with AKs.

In this trial, 20 patients each with ≥4 non-hyperkeratotic AKs on each side of their faces were randomized to receive multiple passes with a microneedling device on one side of their faces, followed by application of aminolevulinic acid HCl to the entire face.

The aminolevulinic acid HCl was allowed to incubate for 1 hour and this was followed by exposure to blue light (Blu U) for 1000 seconds.

For the 19 patients who completed 4 months of follow-up, the mean AK reduction on the microneedling side was 89.3% vs 69.5% on the PDT alone side. In addition, 13 of the 19 patients had a noticeable improved cosmetic appearance on the microneedled side of the face (Spencer, 2016).

No, Its Red

Aminolevulinic acid hydrochloride (BF-200 ALA, Ameluz) was recently approved by the United States Food and Drug Administration for PDT using the BF-RhodoLED lamp, a narrowband, red light illumination source, for lesion-directed and field-directed treatment of AKs of mild-to-moderate severity on the face and scalp.

This approval was based on results from 779 patients with 4-8 mild to moderate AK lesions. The results obtained from these studies demonstrated that BF-200 ALA was significantly superior to the standard of care, with a complete patient response rate of 91% when paired with BF-RhodoLED PDT lamp (CenterWatch, 2017).

In addition, BF-200 ALA showed positive long-term effects with low recurrence over the course of 12 months (Dirschka, 2013).

In a pivotal phase III trial performed on entire treatment fields, BF-200 ALA demonstrated long-lasting skin rejuvenation effects in sun-damaged, but asymptomatic, skin regions (CenterWatch, 2017; Reinhold, 2016).


References

CenterWatch. Ameluz (aminolevulinic acid hydrochloride). 2017. Available at: http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100150/ameluz-aminolevulinic-acid-hydrochloride

Dirschka T, Radny P, Dominicus R, et al. Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis. Br J Dermatol. 2013;168:825-36.

Reinhold U, Dirschka T, Ostendorf R, et al. A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®) ) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED lamp. Br J Dermatol. 2016;175:696-705.

Spencer JM, Freeman SA. Microneedling Prior to Levulan PDT for the Treatment of Actinic Keratoses: A Split-Face, Blinded Trial. J Drugs Dermatol. 2016;15:1072-4.

5-Fluorouracil (5-FU): 4% vs 5% for the Treatment of Actinic Keratosis

While oxymetazoline HCl cream, 1% and bromocriptine gel, 0.33% were not compared in a head-to-head trial, this has been done for 4% 5-FU in an aqueous vehicle cream containing peanut oil (Tolak) vs 5% 5-FU in a vanishing cream (Efudex) in patients with actinic keratosis (AKs).

In a 4-week, double-blind, multicenter non-inferiority study that included 841 subjects, 4% 5-FU cream administered once daily was compared with 5% 5-FU cream twice daily with 100% and 75% clinical clearance of AK’s assessed as the study endpoint.

4% 5-FU achieved 100% clearance in 80% of patients and 75% clearance in 100% of patients compared with 75% and 95%, respectively, with 5% 5-FU.

Skin irritation occurred in 30% of patients treated with 4% 5-FU vs 60% with 5% 5-FU.

It was also noted that the peanut oil component of the 4% 5-FU preparation is safe even in peanut-allergic patients.

Thus, 4% 5-FU is non-inferior to 5% 5-FU with better tolerability and permits once-daily administration which may result in better adherence to therapy (Dohil, 2016).


References

Dohil MA. Efficacy, safety, and tolerability of 4% 5-fluorouracil cream in a novel patented aqueous cream containing peanut oil once daily compared with 5% 5-fluorouracil cream twice daily: meeting the challenge in the treatment of actinic keratosis. J Drugs Dermatol. 2016;15:1218-1224.

Recognizing Unusual Tumors Part 2: Disruptive Technologies for Skin Cancer: Electronic Brachytherapy and Superficial Radiation

Hayes B. Gladstone

As noted in previous sections, a wide range of treatment modalities are available for patients with basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC).  Surgical options include curettage with electrodessication, Mohs micrographic surgery, and surgical excision; and they provide high control rates and generally satisfactory cosmetic results. However, some patients are not suitable candidates for surgery and some cases of non-melanoma skin cancer (NMSC) may not be optimally treated with surgery due to the potential for disfigurement.

Radiation Therapy

Radiation therapy, including external beam and brachytherapy techniques, has been used as primary and post-surgical adjuvant therapy for NMSC and results from published studies have indicated local control ranging from 84-97% with good tolerability (Khan, 2014).

Electronic Brachytherapy

Electronic brachytherapy (EBT) is the administration of high dose rate brachytherapy without the use of a radioactive isotope and with minimal shielding requirements due to the low energies utilized with this system.  This novel approach has been demonstrated to be effective in a large series of 187 patients with 277 NMSC lesions.  At a mean follow-up of 13 months (range = 1-51 months) there were no recurrences. The most frequent acute effects were rash in 90 (44.1%), pruritus in 9 (4.4%) and hyperpigmentation in 4 (2.0%) of 204 lesions evaluated at 1 month after treatment. The most frequent late effects were hypopigmentation in 17 (10.1%) and alopecia in 4 (2.4%) of 168 lesions evaluated at 1 or more years after treatment. Cosmesis at 3 years was excellent for 25 (89.3%) and good for 3 (10.7%) of 28 evaluable lesions; and at 4 years, was excellent for all 6 (100%) evaluable lesions Bhatnagar, 2014).

How would EBT fit into your practice?

  • Personnel:
    • Radiation oncologist
    • Radiation therapist
    • Physicist
  • Treatment:
    • Patient comes into room; portable shield (lead walls not required); machine calibrated and dose parameters set
    • Patient treated
    • Visit takes about 15 minutes twice per week for 8-12 treatments
    • Currently, can be performed in office or at a center

Superficial Radiation: a Different Model

Superficial x-ray therapy (SXRT) has been used by dermatologists for many years and it differs from modern electron beam radiotherapy in that light is the energy source rather than a charged particle. The beam in SXRT is very focused with less collateral tissue damage than EBRT; and the treatment duration is 90 seconds. A retrospective analysis performed on 1715 histologically confirmed primary cutaneous BCC and SCC 2000 and 2010 indicated cumulative recurrence rates for all tumors at 2 and 5 years of 1.9% and 5.0%, respectively.  The recurrence rates for BCC at these evaluations were 2% and 4.2% respectively; and those for SCC were 1.8% and 5.8% (Cognetta, 2012). This approach to treatment for NMSC is appropriate for patients with larger tumors in very cosmetic sensitive areas, those receiving anticoagulants, frail/elderly patients who may not tolerate surgery, and those who refuse surgical intervention.

Dermatologists should be leaders in the use of radiation therapy for the treatment of NMSC.  How do we get there?

  • Develop a method where dermatologists can independently perform EBT and SXRT:
    • Dermatologists are skin cancer experts
    • Dermatologists have historically performed external beam radiotherapy for skin conditions
    • Some dermatologists are currently performing EBT
  • There is a Task Force of Conference of Radiation Control Program Directors:
    • Dermatology is represented
    • Develop guidelines and recommend training for dermatologists in either an independent or hybrid system

 

If we aren’t proactive in advances in skin cancer treatment, then other
specialties will and patients will look elsewhere

 

References

Bhatnagar A. Electronic brachytherapy for the treatment of nonmelanoma skin cancer: results up to 4 years. Int J Radiation Oncol. 2014;90:S756.

Cognetta AB, Howard BM, Heaton HP, Stoddard ER, Hong HG, Green WH. Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients. J Am Acad Dermatol. 2012;67:1235-1241.

Khan L, Breen D, Zhang L, et al. Predictors of recurrence after radiotherapy for non-melanoma skin cancer. Curr Oncol. 2014;21:e326-329.

 

Recognizing Unusual Tumors Part 1: Defining and Managing High-risk Basal Cell and Cutaneous Squamous Cell Carcinoma

Dr. Suneel Chilukuri and Dr. Neil A. Swanson

Basal Cell Carcinoma

Despite the fact that treatment for basal cell carcinoma (BCC) is curative in the vast majority of cases, some patients are at high risk of recurrence and, in a few patients, lesions can progress to a point where local therapy is not possible and the prognosis is quite poor (Puig, 2015).

Characteristics of High-risk Disease

Treatment decisions in patients with BCC are usually made on the basis of estimated risk for recurrence. Aggressive, infiltrating tumors are frequently ulcerated and have ill-defined margins; ulcerated BCC is usually larger than non-ulcerated tumors and may be locally destructive. Risk associated with tumor size varies with location and is defined as >6 mm for the mask area, >1 cm for the cheek, forehead, scalp, and neck, and >2 cm in other body areas. Histological subtype should also be considered in assessing risk for relapse. Morpheaform, sclerosing, infiltrating, desmoplastic, micronodular, basosquamous, keratotic, and metatypical subtypes are associated with higher risk vs superficial and the nodular forms of BCC. Perineural invasion is also associated with a higher risk of relapse; but vascular invasion does not appear influence long-term outcomes.  Importantly, more than 30% of BCCs have mixed pathology, combining less and more aggressive subtypes (e.g., nodular BCC with areas of infiltrating BCC) (Marzuka, 2015; Puig, 2015; Proceddu, 2015).

There is no agreement on the prognostic significance of other factors, such as a previous history of radiotherapy, in patients with BCC.

Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) represents 20% of all non-melanoma skin cancer, and has the ability to metastasize to any organ in the body. It is estimated that cSCC is diagnosed at a rate of 15-35 per 100,000 people and this is expected to increase 2-4 % per year (Burton, 2016).

Risk and Staging cSCC

Although most sSCC are easily cured, there is a high-risk subset with an increased risk of metastasis and death (Karia, 2014). Factors believed to be associated with higher risk cSCC include location on the ear, lip, or genitalia; poorly differentiated, acantholytic desmoplastic, or adenoid squamous histology; perineural invasion; and clinical features that include rapid growth, pain, paresthesias, invasion to bone, and cranial nerve involvement.

Despite identification of individual factors associated with higher risk cSCC, there is no consensus definition of high-risk disease and there is limited published information on best approaches to treatment.  At present, these high-risk patients are typically managed with a multidisciplinary approach decided on a case-by-case based on tumor board discussions. Several clinical and histologic risk factors are associated with increased risk of recurrence, metastasis, and death in patients with cSCC, but high-risk cSCC has not been consistently defined, nor has associated prognosis been estimated (Karia, 2014).  There are multiple staging systems for SCC, including those from the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) and a more recently developed system developed at the Brigham and Women’s Hospital (BWH) (Jambusaria-Pahlajani, 2013; Karia, 2014). A comparison of these systems indicated that current UICC and AJCC tumor (T) staging fail to identify high-risk sSCC because the majority of poor outcomes occur in low T stages and heterogeneous tumors with diverse risk profiles. Conversely, the BWH system has four statistically distinct stages and enhanced ability to appropriately upstage high-risk tumors from low to high stages (Karia, 2014).

What to do in defining risk in your patients with BCC or cSCC:

  • Consider clinical presentation and histology
  • Be aware of a new validated approach to staging patients with SCC.

Interventions in cSCC and BCC

Retinoids for Prevention Treatment of Skin Cancer

Systemic retinoids have been shown to be effective for the prevention of skin cancer (Tilley, 2015); and initiation of prophylaxis is indicated to prevent morbidity from multiple primary tumors and to decrease the risk of death from high-risk tumors.  Candidates for retinoid administration include patients with xeroderma pigmentosum, basal cell nevus syndrome, or severe sun damage; and patients who are immunosuppressed for solid organ transplantation or with chronic lymphocytic leukemia (Reilly, 2004).

Delivering retinoids for skin cancer prevention – practical considerations:

  • Start Low: 10 mg/day
  • Gradually increase the dose to 20-30 mg/day
  • Titrate the dose to prevent/manage side effects (chelitis, skin peeling, scalp alopecia, hyperotosis, hyperlipidemia)
  • Understand that this is potentially life-long treatment and educate your patient
  • Drug holidays may help to treat transient side effects
  • Try to decrease immunosuppression in conjunction with this treatment
  • Be aware of risk for elevations in triglycerides and hepatic transaminases

Smoothened Inhibitors in the Treatment of BCC and Risk for cSCC

The smoothened inhibitors, vismodegib and sonidegib, have been shown to be highly effective for the treatment of patients with advanced BCC (e.g., Sekulic, 2012; Migden, 2015); and many new agents from this class (e.g., saridegib, CUR61414, BMS-833923, LEQ506, PF-04449913, TAK-441) are in development for the treatment of BCC and other cancers. However, extensive use of vismodegib in patients with BCC has been associated with increased risk for the development of cSCC.  Case reports have described emergence of new-onset keratoacanthomas and cSCCs in patients with advanced BCCs during vismodegib therapy (Aasi, 2013; Orouji, 2014); and results from a recent case-control study carried out at the Stanford Medical Center which included 180 patients indicated that treatment of BCC with vismodegib was associated with a >6-fold increase in the risk for cSCC (Mohan, 2016).  The mechanism(s) underlying this phenomenon are not understood, but it has been suggested that smoothened inhibition may inadvertently activate the RAS/MAPK pathway, thereby promoting tumorigenesis (Zhao, 2015).

What to remember and what to do:

  • BCC with apparent resistance to vismodegib may actually be newly developed cSCC
  • Perform new biopsies whenever in doubt about new and/or progressive skin lesions in patients receiving hedgehog pathway inhibitors
  • Patients with advanced BCCs who are considering vismodegib should be advised that this treatment seems to increase the risk for subsequent cSCC

References

Aasi S, Silkiss R, Tang JY, et al. New onset of keratoacanthomas after vismodegib treatment for locally advanced basal cell carcinomas: a report of 2 cases. JAMA Dermatol. 2013;149:242-243.

Burton KA, Ashack KA, Khachemoune A. Cutaneous squamous cell carcinoma: a review of high-risk and metastatic disease. Am J Clin Dermatol. 2016 Jun 29. [Epub ahead of print].

Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013;149:402-410.

Karia PS, Jambusaria-Pahlajani A, Harrington DP, Murphy GF, Qureshi AA, Schmults CD. Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol. 2014;32:327-334.

Marzuka AG, Book SE. Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. Yale J Biol Med. 2015;88:167-179.

Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716-728.

Mohan SV, Chang J, Li S, Henry AS, Wood DJ, Chang AL. Increased risk of cutaneous squamous cell carcinoma after vismodegib therapy for basal cell carcinoma. JAMA Dermatol. 2016;152:527-532.

Orouji A, Goerdt S, Utikal J, Leverkus M. Multiple highly and moderately differentiated squamous cell carcinomas of the skin during vismodegib treatment of inoperable basal cell carcinomas. Br J Dermatol. 2014;171:431-433.

Porceddu SV. Prognostic factors and the role of adjuvant radiation therapy in non-melanoma skin cancer of the head and neck. Am Soc Clin Oncol Educ Book. 2015:e513-518.

Puig S, Berrocal A. Management of high-risk and advanced basal cell carcinoma. Clin Transl Oncol. 2015;17:497-503.

Reilly P, DiGiovanna JJ. Retinoid chemoprevention in high-risk skin cancer patients. Dermatol Nurs. 2004;16:117-120, 123-126; quiz 127.

Sekulic A, Migden MR, Oro AE, et al Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171-2179.

Zhao X, Ponomaryov T, Ornell KJ, et al. RAS/MAPK activation drives resistance to Smo inhibition, metastasis, and tumor evolution in Shh pathway-dependent tumors. Cancer Res. 2015;75:3623-3635.